Objective To investigate thrombomodulin (TM), thrombin-antithrombin complex (TAT), α2-plasmin inhibitor-plasmin complex (PIC) and tissue plasminogen activator-inhibitor complex (t-PAIC) in assessing the risk and prognosis of venous thromboembolism (VTE) in critically ill patients. Methods This study retrospectively analyzed the data of 254 critically ill patients admitted to the ICU of our hospital from October 2020 to November 2022. Fasting venous blood levels of TAT, PIC, TM and t-PAIC were measured using a highly sensitive chemiluminescent enzyme immunoassay. The relationship between TAT, PIC, TM, t-PAIC and VTE was analyzed using binary logistic regression. Receiver operating characteristic (ROC) curves were used to evaluate their diagnostic efficiency in differentiating VTE. The 28-day survival of patients was estimated using the Kaplan-Meier method. Results Among the 254 patients, 106 (41.7%) developed VTE, including 16.5% with pulmonary thromboembolism, 20.5% with deep vein thrombosis, and 4.7% with other (catheter or superficial vein) thrombosis. Compared with the non-VTE group, the levels of TAT, PIC, TM, t-PAIC, D-dimer, and fibrin degradation product in the VTE group were significantly increased (all P＜0.05) Multivariate analysis showed that TAT, PIC, TM, and t-PAIC were closely related to VTE in critically ill patients (P＜0.05)Among the four coagulation markers, the lowest area under the curve (AUC) of tPAIC was 0.615 and the highest AUC of TAT was 0.711. When the combination of TAT, PIC, TM, t-PAIC was applied, the AUC increased to 0.814 and the sensitivity increased to 74.1%. Among the four coagulation markers, the 28-day survival rate of patients with high levels of TAT, PIC and TM was significantly lower than that of patients with low levels (P＜0.05) Conclusion The combination of TAT, PIC, TM and t-PAIC is superior to the application of single marker in the diagnosis of VTE in critically ill patients